Investigating new causes of inherited kidney disease

While genome sequencing can rapidly examine all genes in such a patient, the number of genetic changes present in any individual makes the process of identifying a causative mutation challenging. This limits our capacity to move from novel gene back into clinical practice and patient outcomes. The dilemma is twofold: can we be sure that a novel genetic change causes disease and what value is this information to the patient and their family? To address these issues, we need to develop effective research genomics approaches to identify likely changes in the millions of bases of sequence from a patient as well as functional disease models which are capable of validating the association between any novel mutation and the disease phenotype.

Research Genomics
Genome sequencing of any individual will reveal in the order of 25,000 single nucleotide polymorphisms (SNPs). We have developed a pipeline of bioinformatic analysis that investigates these many variations to exclude those previously identified as non-pathogenic, not predicted to affect the encoded protein (silent or intergenic) or, based on comparison with the genomes of unaffected relatives, not associating with the phenotype in a manner consistent with the pattern of inheritance. This allows a rapid refinement of likely ‘private’ causative mutations. 

Disease Modelling
We have developed a method whereby patient-derived induced pluripotent stem cells (iPSC) can be differentiated in vitro to form mini-kidneys. These mini-kidneys contain all the anticipated components of the developing organ, including collecting ducts, nephrons and their surrounding interstitium and vasculature. We hypothesise that such organoids will i) provide a rapid validation that a novel gene is the causative mutation and ii) represent an accurate disease model by which to interrogate the pathways affected as a result of mutation. The advent of genome engineering approaches utilising the CRISPR/Cas9 technology mean that we can rapidly and efficiently generate organismal models carrying the exact variant of interest present in our patients.  Both cellular and organismal models may be able to inform us

Presentations and Publications 
Publications
Mallett AJ, McCarthy HJ, Ho G, Holman K, Farnsworth E, Patel C, Fletcher JT, Mallawaarachchi A, Quinlan C, Bennetts B, Alexander SI. Massively parallel sequencing and targeted exomes in familial kidney disease can diagnose underlying genetic disorders Kidney International, Dec 2017, 92(6):1493-1506

Ng M, Mcclymont K, McCallum N, Dua R, Holman K, Bennetts B, Ho G, Patel C, Mallett A., CFHR5 nephropathy in a Greek-Cypriot Australian family: ancestry-informed precision medicine. In Press, accepted 17th April 2018, Kidney International Reports.

Jayasinghe K, Quinlan C, Stark Z, Patel C, Sampson MG, Saleem M, Mallett AJ. Meeting Report of the 2017 KidGen Renal Genetics Symposium Human Genomics, Jan 2018, 12:5

Jayasinghe K, Quinlan C, Stark Z, Patel C, Wardrop L, Kerr PG, Trnka P, Mallett AJ on behalf of the KidGen Collaborative Renal Genetics in Australia: Kidney Medicine in the Genomic Age, Nephrology, March 2019 24:3  https://doi.org/10.1111/nep.13494

Little ML and Quinlan CM - Advances in our understanding of genetic kidney disease using kidney organoids. Paediatric Nephrology 2019 May 7 doi: 10.1007/s00467-019-04259-x
Presentations
​Mallett et al. “Evaluating an Australian national network of multidisciplinary renal genetics clinics: the KidGen collaborative” Informational Poster at American Society of Nephrology Kidney Week
Andrew Mallett and Cathy Quinlan “Update on progress of KidGen Australian Genomics Flagships” Invited presentation 2018 Renal Genetics Symposium – Renal Genomics Translating the Potential.
Hossai Gul “Integrating genomics into routine clinical care using implementation science: a mixed method longitudinal study of renal genetics clinics around Australia. Oral presentation of abstract at 2018 Renal Genetics Symposium – Renal Genomics Translating the Potential.
Jayasinghe K, Implementing genomics into adult nephrology services a review of the literature and study protocol, Oral abstract presentation at Renal Genetics Symposium – Renal Genomics – Translating the potential Sydney 2018 – Awarded best oral abstract of symposium.
Talbot A, The prevalence and impact of inherited renal disease at the Royal Melbourne Hospital Oral abstract presentation at Renal Genetics Symposium – Renal Genomics – Translating the potential Sydney 2018
McPherson E, Variation and value of interdisciplinary models of care delivery in renal genetics services Oral abstract presentation at Renal Genetics Symposium – Renal Genomics – Translating the potential Sydney 2018